Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

Abstract

Accumulating evidence reveal important applications of endogenous pain modulation assessment in healthy controls and in patients in clinical settings, as dysregulations in the balance of pain modulatory circuits may facilitate pain and promote chronification of pain. This article reviews data on pain modulation, focusing on the mechanisms and translational aspects of pain modulation from conditioned pain modulation (CPM) to placebo and nocebo effects in experimental and clinical pain. The specific roles of expectations, learning, neural and neurophysiological mechanisms of the central nervous system are briefly reviewed herein. The interaction between CPM and placebo systems in pain inhibitory pathways is highly relevant in the clinic and in randomized controlled trials yet remains to be clarified. Examples of clinical implications of CPM and its relationship to placebo and nocebo effects are provided. A greater understanding of the role of pain modulation in various pain states can help characterize the manifestation and development of chronic pain and assist in predicting the response to pain-relieving treatments. Placebo and nocebo effects, intrinsic to every treatment, can be used to develop personalized therapeutic approaches that improve clinical outcomes while limiting unwanted effects.

Delayed effects of attention on pain sensitivity and conditioned pain modulation

“…In accordance with the hypothesis, the results show that VAS scores were lower during Stroop sessions compared to sessions with stimulus‐evoked pain without Stroop and with no differences between Stroop‐pain and Stroop‐pain‐conditioning. These results support top‐down analgesia possibly derived via cortical and/or subcortical regions (Damien, Colloca, Bellei‐Rodriguez, & Marchand, ; Wiech, ), and align with the existing literature showing that Stroop is sufficient to reduce pain sensitivity in healthy participants (Bantick et al., ; Fechir et al., ; Martinsen et al., , ; Oosterman et al., ; Wilder‐Smith et al., ) although one study found increased pain with increased cognitive load (Silvestrini & Rainville, ) and no significant difference in pain sensitivity was found in another study (Aniskin et al., ). Of previous studies only three looked at differences between congruent and incongruent paradigms with regards to pain sensitivity (Bantick et al., ; Martinsen et al., , ) and a difference was only found in one of the three (Bantick et al., ).…”

<p>Remote Analgesic Effects Of Conventional Transcutaneous Electrical Nerve Stimulation: A Scientific And Clinical Review With A Focus On Chronic Pain</p>

“…64 CPM is a form of central pain regulation that integrates sensory and pain signals from the entire body. [65][66][67] This analgesic mechanism decreases nociceptive signal transmission in the spinal cord through supraspinal-mediated descending inhibition. CPM can be triggered by remote noxious 65,68 and nonnoxious 24,47,[68][69][70] conditioning stimuli.…”

“…27 Activation of supraspinal descending pain controls, which have inherently diffuse inhibitory effects, may explain the remote segmental and extrasegmental effects of conventional TENS. 3,22,24,66,79,80 Finally, activation of brain areas comprising the pain matrix 76,77 could have profoundly widespread analgesic effects, as well as improve mood, sleep, and other functions. 25,26,81 Various neurotransmitters are involved in pain inhibition, including GABA, glycine, noradrenaline, serotonin, and opioids.…”

“…79,128 Like TENS, the placebo response is partially mediated though descending pain inhibition. 66,167 However, placebo responses are unlikely to account completely for the remote analgesic effects of conventional TENS. First, the existence of robust animal and human experimental pain data, which are less sensitive to placebo than clinical pain, 168,169 argues against a primary role for a placebo mechanism.…”

Preface

“…Which are the CNS mechanisms that are in common between placebo effects and other forms of pain modulation such as conditioned pain modulation (CPM) and the diffuse noxious inhibitory control (DNIC)? These and other questions are addressed in a comprehensive overview of the CPM mechanisms and their clinical relevance (Damien, Colloca, Belleï-Rodriguez, & Marchand, 2018). It has been speculated that patients who present less efficient CPM might need treatments that restore central and peripheral pain inhibitory processes (Colloca et al, 2017).…”